Multiple generator elution system

ABSTRACT

A multiple generator elution system for selectively eluting from a plurality of parent-daughter generators according to an elution schedule it calculates taking into account supply data, demand data, and available activity in each of the generators.

FIELD OF THE INVENTION

The present invention relates to the field of radioisotope generators.More specifically, the present invention is directed to a multiplegenerator elution system.

BACKGROUND OF THE INVENTION

Fission-produced Mo-99 supply is in a state of uncertainty. Only tworeactors, the Canadian NRU reactor and the Petten HFR reactor, representapproximately 60-70% of the world's supply of fission produced Mo-99.When either of these reactors goes off-line, whether for scheduledmaintenance or for unscheduled repairs, the result is to effectivelyreduce nuclear medicine procedures to only essential cases. All thereactors used to manufacture fission Mo-99 are nearing the end of theirrespective working lives, currently only one replacement reactor isplanned, the Petten replacement called Pallas. Of additional concern isthe proliferation of highly enriched uranium (HEU), the target materialfor fission Mo-99, falling into the hands of terrorists or roguegovernments. HEU is used for manufacturing nuclear weapons.

Alternatively, a gel-based generator uses Mo-99 obtained from neutronactivation (n,γ) of natural molybdenum, which can be performed in anynuclear reactor including power reactors. Unfortunately, Mo-99 producedfrom n,γ methods tends to be of low specific activity when compared toMo-99 produced from fission of U-235, whether HEU or low enricheduranium (LEU). Low specific activity means the Mo-99 must be eitherplaced on a very large alumina column to absorb all the inactivemolybdenum, or turned into an insoluble gel matrix that reduces theoverall volume of the elutable column (e.g. zirconium molybdate ortitanium molybdate). Subsequently, large elution volumes are required toelute the column of the Tc-99m daughter nuclide, particularly if analumina column is used. The prior art fails to address all of the issuesencountered with low specific activity and or low activity generators.

Nucl. Med. Comm., 25 609-614 (2004) discusses the need to obtain highradioactive concentrations of Tc-99m from zirconium molybdate gelgenerators (higher concentrations are often required for “cold kit”compounding, as well as economic reasons in larger radiopharmacies).

U.S. Pat. No. 5,729,821 discloses a method for concentration of Tc-99mfrom Mo-99 sorbent on an alumina based column. The system requiresmultiple columns to achieve concentration of the eluate. Multiplecolumns must be used because the Tc-99m is eluted off the primary columnby means of ion exchange with the chloride ion in saline. The cation(sodium) is then removed by the secondary column (in this case a silverhalide based), and the pertechnetate is concentrated in the tertiaryanion column for subsequent elution with saline to form sodiumpertechnetate. This method requires the use of an acid salt or weak acidto separate and elute Tc-99m from the parent nuclideMo-99 (e.g. aluminacolumns), as well as a cation ion column to remove the cation from theelution, so that the pertechnetate ion can be concentrated on an anioncolumn.

Applied Radiation and Isotopes 66 (2008) 1814-1817 discloses a methodwhich extracts Tc-99m from a solution containing Mo-99. This is acomplicated procedure that requires the use of organic solvents(tetrabutylammonium bromide solution in methylene chloride) to extractand concentrate the Tc-99m.

Applied Radiation and Isotope 66 (2008) 1295-1299 discloses a methodcited which is a variant of the above method where a low specificactivity alumina based generator is eluted with saline to remove theTc-99m. The eluate is concentrated on strong anion exchanger Dowexcolumn. The Tc-99m is removed by elution with tetrabutylammonium bromidesolution with methylene chloride into a collected in a vial. The organicsolvent is removed by vacuum pumping to dryness and reconstituted withsaline for use with cold kits. This method is impractical because oftime required to prepare the concentrated Tc-99m.

U.S. Pat. No. 6,157,036 discloses a method for low specific activity ionexchange type generators (i.e. alumina). The system uses multiplecolumns similar in method to U.S. Pat. No. 5,729,821. The method usespositive pressure instead of safer negative pressure to movefluids—negative pressure (vacuum) is inherently safer for transfersinvolving radioactive materials.

There is therefore a need for a system which manages grow-in of thedaughter nuclide for efficiency purposes. There is also a need in theart for an elution system which minimizes the waste and maximizes theuse of the daughter nuclide produced by a series of generators. There isfurther a need for an elution system which can reduce the risk ofproliferation of HEU. There is also a need for a manifold kit which isoperable by an automated actuation system for directing the eluate froma series of generators to a collection vial.

SUMMARY OF THE INVENTION

In view of the needs of the art, the present invention provides amultiple generator elution system, comprising a plurality ofparent-daughter nuclei generators and a control system for tracking thegrow-in of the activity of each of the parent-daughter nucleigenerators.

The control system receives demand data indicating requirements foractivity production and is configured to elute from selected ones of thegenerators with a first eluate in order to provide a desired amount of adaughter nuclide. A receiving unit receives demand data which includesat least an amount of daughter nuclide to be produced and a schedule forthe production of the amount of daughter nuclide. The receiving unit isoperable with the control system so that the control system willschedule the elution of the daughter nuclide from the plurality ofgenerators to meet the demand represented by the demand data. Thereceiving unit will also receive supply data

The present invention also provides a concentration column forcollecting the generator daughter nuclide from the selected ones of theplurality of generators. The concentration column contains anappropriate column media. For example, when the daughter nuclide isTc-99m, concentration column is desirably an anion column from which thedaughter nuclide is eluted. Also provided is a collection container forreceiving the daughter nuclide from said concentration column.

Additionally, the present invention provides a control system a multiplegenerator elution system which tracks the grow-in of the activity ofeach of the parent-daughter nuclei generators and schedules elution fromamong the generators to meet an inputted demand for the daughternuclide.

The present invention may also provide a source of second eluent toelute the columns. Depending on the application, the second eluent maybe different from the first eluent or both may be the same.Additionally, in embodiments where the same eluent is used to elute boththe generators and the concentration column, the eluent may be drawnfrom a single source. Alternatively, the source of first eluent may beprovided individually to each generator, rather than from a commonsource. The present invention also provides that when highly pure water,such as water for injection, is provided from a common reservoir foreluting the generators, this water may also be used to rinse thecomponents of the elution system between elution runs. The presentinvention also contemplates that a source of highly pure water may beprovided only for the purpose of rinsing components of the multiplegenerator elution system.

Additionally still, the present invention provides a method foroperating a multiple generator elution system which coordinates inputteddemand data for the daughter nuclide produced by the generators, tracksthe available activity in each of the generators over time, andschedules elution from among the generators to meet the inputted demandfor the daughter nuclide.

Furthermore, the present invention provides a kit for a manifold systemwhich may be operated by a control system to direct the elutions fromamong a plurality of parent-daughter generators to a separations column.

The present invention solves problems for those skilled in managing andoperating generators in a nuclear pharmacy. Using Tc-99m/Mo-99 generatorfor purposes of illustration, and not of limitation, the presetinvention combines and concentrates the daughter nuclide technetium[Tc-99m] pertechnetate elutions from multiple generator units andextends the useful life of decayed or low activity generators. Thepresent invention automatically manages the isotope “grow-in” formaximum efficiency and cost savings, in conjunction with demand datafrom an ERP system or manual inputs. The present invention also allowsoperating personnel to model “what-if” scenarios such as when modelingsupply shortages and unexpected increases in demand. Additionally, thepresent invention may be housed behind a radiological shielding thatsafely stores generators, as well as all components handlingradioactivity. The present invention allows a gamma gel based Mo-99generators to be more operationally competitive with fission basedgenerators, thus facilitating a viable alternative to Mo-99 produced bythe irradiation of highly enriched uranium (HEU), and thus reducing theproliferation of nuclear bomb grade material. Moreover, the presentinvention provides prescription compounding data interchange forelectronic medical records.

The Mo-99 isotope used in Tc-99m/Mo-99 generators typically represents75% or more of the total cost of a generator. Generator and isotopepurchases are typically the largest single expense item. Mo-99 decaysinto Tc-99m at a known exponential rate, Tc-99m also decays at a knownexponential rate. A typical generator contains a known amount activitywhen delivered. When the generator is eluted the Tc-99m is removedleaving the Mo-99 behind to continue to decay into Tc-99m. Thecalculations required to accurately determine the amount of availableTc-99m on a generator at any given time are very complex, and not easilyperformed. The present invention provides a control system incorporatingsoftware for easily and quickly executes these calculations. Utilizingthis software in conjunction with the multiple generator elution systemallows the control system to select an efficient combination ofgenerators for any given demand. Additionally, historical or real-timedemand can be obtained by either manual operator entry, or by data linkfrom an enterprise resource planning system.

A titanium molybdate “gel” based generator uses very low specificactivity Mo-99, which leads to elutions that are less concentrated andof generally lower total radioactive content than the industry standardfission Mo-99 based generator. The multiple generator elution system ofthe present invention eliminates these issues allowing the gel-basedgenerator to be more operationally competitive than the industrystandard fission based generator.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a cross-sectional schematic of a parent-daughter generator ofthe prior art.

FIG. 2 depicts an activity decay curve for a Mo-99/Tc-99m generator.

FIG. 3 depicts the decay curve for Tc-99m in a Mo-99/Tc-99m generatorafter serial elutions of the Tc99m isotope ions.

FIG. 4 depicts a multiple generator elution system for gel-based Mo-99generators.

FIG. 5 depicts an alternate representation of the elution system of FIG.4.

FIG. 6 depicts a multiple generator elution system for alumna-basedMo-99 generators.

FIG. 7 depicts an alternate representation of the elution system of FIG.6.

FIG. 8 depicts a cassette-based manifold as part of a multiple generatorelution system of the present invention.

FIG. 9 is a flow-chart depicting a method of the present invention.

FIG. 10 depicts a screen shot of a graphical user interface (GUI) of thepresent invention for providing supply information for a multiplegenerator elution system of the present invention.

FIG. 11 depicts a screen shot of a GUI for an elution management systemfor a multiple generator elution system.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention concentrates eluates from large volume elutionsfor reconstitution with “cold kits” that require higher radioactiveconcentrations. In one embodiment, the present invention provides asystem for concentrating Tc-99m. The present invention can concentrateeluates in larger radiopharmacies to achieve work flow efficiencies,particularly with QC testing of eluates, and eliminates time consumedeluting multiple generators individually. Additionally, the presentinvention allows generators nearing expiry, which tend not to be usedbecause of low yields and thus lower radioactive concentration ofeluate, to be more fully utilized to expiry, achieving cost savings. Thepresent invention incorporates software to better match demand withsupply, thus achieving cost savings and minimizing waste and loss. Thepresent invention obviates the need for using organic solvents, thuseliminating waste and use of hazardous organic solvents.

The present invention provides a multiple generator elution system whichuses multiple parent-daughter generators, tracks the in-growthrelationship for the parent-daughter isotopes in each of the generators,and concentrates the output of the generators which are eluted. Bringingall three of these concepts together solves inherent issues with lowspecific activity generators, in both in application and efficiency ofuse.

The multiple generator elution system is desirably enclosed within aradiation-shielding enclosure, such as a lead-walled hot cell. While thepresent invention would work for managing elution from a singlegenerator, in the preferred embodiment, multiple generators are managed.One embodiment of the present invention utilizes a number of Mo-99titanium/ Tc-99m titanium [Mo-99] molybdate gel generators utilizingMo-99 obtained from neutron activation of natural molybdenum (n,γMo-99). While particular reference is made to managing the elutions fromMo-99/Tc-99m parent-daughter generators, the present inventioncontemplates that other types of generators may also be employed toelute and other daughter isotopes, or daughter nuclides.

Thus in one embodiment of the present invention, a lead-shieldedenclosure contains 1 or more Mo99/Tc99m generators. The generators areconnected together via a fluid path system, which enables anycombination of generator to be eluted onto a concentration column orcolumns. In the case of Tc-99m, the concentration column is an anioncolumn. The concentrated Tc99m is subsequently eluted off theconcentration column into a collection vial at the required radioactiveconcentration ready for use in the radio-pharmacy. The control systemselects the most efficient combination of generators based on demand,available supply and future demand.

Both the available supply of activity and the current and future demandfor activity may be manually entered or electronically transferred intothe receiving unit and into the control system from the generatorsthemselves and from the radio-pharmacy Enterprise Resource Planning(ERP) system, respectively. For example, data transferred from thegenerators themselves could be electronically read or scanned from alabel on the generator, such as a bar code. Such data regarding thegenerators, also called the ‘supply data’, can include the calibrationdata for the generator, providing both date and activity. Additionallythe supply data is contemplated to include the time and date that thegenerator is available for use and the time and date of the firstelution off set. Similarly, the demand data, including the requiredactivity and the time such activity is required from the system may beeither manually or electronically entered into the control system. Thepresent invention contemplates that a data receiving unit is configuredfor the manual and/or electronic input of the demand data.

Using the supply data, the control system can calculate the availableactivity in each generator, desirably in set intervals, e.g. everythirty minutes, and displays the same to an operator. The demand data isdesirably similarly displayed over the same time intervals as the supplydata. The control system includes a computer to calculate the best fitelution profile, or schedule, for selecting which of the availablegenerators will be eluted at a given time to meet the demand data in themost efficient way possible, thus maximizing the useful life of eachgenerator and minimizing waste. The control system is desirablyprogrammed to perform a Generalized Reduced Gradient Algorithm analysisof the demand data and the activity levels of the plurality ofgenerators to determine the optimum elution schedule for minimizingwaste. Alternatively, the present invention contemplates that thecontrol system is programmed to run simulations of various elutionschedules from the plurality of generators and selecting the elutionschedule resulting in the lowest amount of waste of the daughter nuclideupon meeting the demand data. The elution schedule will also be providedto the operator.

Desirably, the display of the elution schedule is provided on a GUIwhich gives the operator the option of overriding the calculatedoptimized elution schedule by instead scheduling different generatorsfor elution at a given time. When the operator decides to modify theelution schedule, the control system will recalculate the elutionschedule and display the both the updated activity availability overtime for each generator as well as the scheduled time of elution fromeach of the generators. If the updated elution schedule is satisfactoryto the operator, the elution instructions will be followed for elutingthe selected generators according the schedule. In this way, the presentinvention provides the option of an ‘operator-in-the-loop’ to overseeand manage the elution from the generators and allow the operator tooverride the calculated schedule. Alternatively, the present inventionis able to operate without the need for operator intervention and canthus perform the scheduled elutions automatically without operatorinput, thereby freeing the operator to tend to other pharmacy duties.

The elution instructions will be used to electronically control theelution of the selected generators. As the generators are eluted, thecontrol system will update the ingrowth calculations and update theelution schedule if necessary. The present invention contemplates thateither an operator or the system will perform the step of confirmingthat the selected generators were in fact eluted.

Calculations used in populating the elution schedule will desirably takeinto account known constants such as the parent nuclide half-life anddecay equation, the daughter nuclide half life and decay equation, theelution yield efficiency as well as the fraction of the elutionavailable the parent nuclide decay. Additionally the control system willconsider the equilibrium equation for the parent-daughter and theexpiration time for the generator. Most generators have a 2 weeklife—this is a pharmaceutical expiry requirement—but it could be muchlonger if the parent isotope has a long half life, e.g., Sr-90/Y-90

The present invention offers numerous advantages both technically andeconomically. The present invention is thus able to perform as aconcentrator of the activity eluted from the selected generators foreach elution run. Not only does this allow the efficient utilization ofthe generators, but it also allows that generators nearing expiry canstill be utilized in combination with each other as their activities areconcentrated together. Automated operations can reduce exposure to thedoses by the pharmacy staff. Labor efficiencies are realized as well.For example, if four generators are to be individually eluted, then fourdistinct quality control tests are required. The present invention, byconcentrating the individual elutions, allows that only a single qualitycontrol test be performed on the concentrated elutions, allowing formore activity to be retained in the collection vial for clinical use.

The present invention makes the use of gel generators a commerciallyviable option, despite their lower comparative specific activity tofission generators. The multiple generator elution system (MGES) of thepresent invention is intended to eliminate the disadvantages of gelbased generator systems discussed above. Additionally, the use of gelgenerators improves the management of isotope supply during outages orshortages by the conventional sources.

The system desirably includes a shielded area that houses two or moregel generators. These generators are connected to separate valvemanifolds, which can be selected by the control system to elute theselected generator(s) at the appropriate time to meet planned demand.The Tc-99m is eluted by passing an eluent through the selected one ormore generators. The Tc-99m is collected on an alumina concentrationcolumn. When the collection(s) from the generator(s) is complete, thecontrol system elutes the concentration column with eluent into anindustry standard shielded collection vial. The eluent can be drawn froma reservoir or from individual saline vials currently used to elutegenerators.

All the fluid paths, concentration column, and collection vial equipmentare desirably shielded by a hotcell to provide radiological protectionto the operators. Shielding of individual components may be alsoprovided within the radiation-shielding hot cell.

Various methods of concentrating Tc-99m elutions have been documented.The calculations for determining the in-growth relationship for parentdaughter isotopes are widely known, but not often used because ofcomplexity. The use of n,γ Mo-99 in gel generators systems and othergenerator systems is also known. The present invention brings all threeof these concepts together into a single elution system that manages thesupply data, the available activity, and demand data for a plurality ofgenerators, and overcomes issues inherent with low specific activitygenerators, in both in application and efficiency of use.

The present invention will work with zirconium or titanium molybdate gelgenerator systems. With modification, the present invention (asdetailed) will work with alumina based systems as well. To work withalumina based systems additional columns and fluid paths therefore willbe required.

The concept of a titanium molybdate gel generator design has beenproven. The gel is produced post irradiation from irradiated naturalmolybdenum metal. The established method includes irradiating the preformed gel or molybdenum trioxide. Irradiating metal offers yield,safety, and processing efficiency advantages.

Referring now to FIG. 1, a parent-daughter generator 110 of the priorart and incorporated into the multiple generator elution system of thepresent invention includes a long-lived parent nuclide that decays to ashorter-life daughter nuclide. As the parent and daughter nucludes arenot isotopes, it is possible to chemically isolate the daughter nuclide.An eluent is directed through a column containing the parent anddaughter nuclides, but carries off only the daughter nuclide as eluatefrom the column. After the elution, the parent nuclide (remaining in thegenerator) will decay to provide a fresh supply of daughter nuclide. Thegenerator is thus able to provide a fresh supply of daughter nuclide asneeded until the parent activity is depleted.

Generator 110 includes a generator body 112 formed from aradiation-shielding material such as lead. Generator body 112 defines acolumn cavity 114 containing a column 116 holding the parent nuclide.Generator body 112 defines an elongate eluent channel 118 and anelongate eluate channel 120 extending in fluid communication betweencolumn cavity 114 and an eluent cavity 122 and a collection cavity 124,respectively. Column 116 contains a media 126 to which the parentnuclide binds but from which the daughter nuclide therein may be eluted.Eluent cavity 122 supports an eluent vial 130 and collection cavity 124supports a collection vial 132 therein. An eluent conduit 134 extends influid communication between eluent vial 130 and column 116 so as todeliver the eluent from within vial 130 into column 116. At each end,eluent conduit 134 terminates in an elongate needle 125 a and 125 b forpuncturing septums of vial 130 and column 116, respectively. An eluateconduit 136 extends from column 116 to collection vial 132 so as todeliver the eluate from column 116 into vial 132. At each end, eluateconduit 136 terminates in an elongate needle 129 a and 129 b forpuncturing septums of vial 132 and column 116, respectively. Typically,collection vial 132 is an evacuated vial so that the low pressure withinthe vial draws the eluent fluid from eluent vial 130, through column 116and thereinto. A separate air inlet conduit 140 extends in fluidcommunication between eluent vial 116 and an air intake filter 142 so asto assist the evacuation of the eluent from eluent vial 130. Typically,collection vial 132 is housed within its own radiation shield 144 suchthat removal of shield 144 from collection cavity 124 will carry thenow-filled collection vial 132 with it to where a pharmacist maywithdraw the collected eluate for further processing.

In one embodiment, column 116 contains Mo-99 which decays into Tc-99mwith acidic alumina as the sorbent. Column 116 would then be an acidicalumina column although other types of columns, as previously described,may also be used. The present invention contemplates incorporatingmultiple generators 110. As will be shown hereinbelow, the presentinvention further contemplates providing that the collection vials arereplaced for each generator with a conduit leading to a commoncollection vial. Additionally, the present invention contemplates thatinstead of each generator having its own eluent vial 130, a commonsource of eluent may be provided which may be directed to any and all ofthe generators as required. For example, when column 116 is an acidicalumina column with Mo-99, eluent vial 130 may provide a source ofsaline for eluting the Tc-99m nuclide from the column. Alternatively,for example, for a gel generator, a source of water for injection may beprovided as an eluent.

The present invention contemplates that the generators used by thepresent invention may be either a fission or n,γ generator. For example,the TechneLite® (Technetium Tc99m Generator) sold by Lantheus MedicalImaging, 331 Treble Cove Rd., N. Billerica, Mass. 01862, USA may beused. The TechneLite generator is what is known as a dry generator,which means that it has an external source of saline to elute thesystem. Most generators tend to be in this format. Similar to otherfission based generators the TechnelLite generator is based on acidicalumina column to facilitate the storage of Mo-99 and subsequentseparation of the daughter isotope Tc-99m. Similarly, generator 110 maycomprise the Ultra-Technekow™ DTE (Technetium Tc-99m Generator sold byCoviden (Mallinckrodt Inc., 2703 Wagner Place, Maryland Heights, Mo.63043, USA. The Ultra-Technekow is very similar to the TechneLite unit.Alternatively still, the DryTec® (Technetium Tc99m Generator may be usedwith the instant invention. The Drytec generator is sold by GEHealthcare, The Grove Centre, White Lion Road, Little Chalfont,Buckinghamshire HP7 9LL, UK, and is similar to the other fissiongenerators listed above.

Moreover, generator 110 may be an n,γ, or gel, generator. One gelgenerator is the Tc-99m—Geltech Generator sold by the Government ofIndia Dept of Atomic Energy, BRIT/BARC Vashi Complex, Sector-20 Vashi,Navi Mumbai—400 705, India. The Geltech generator for 99mTc is a dualcolumn system comprising of a primary Zirconium Molybdate-99Mo gelcolumn and a secondary purification Acidic Alumina column. These typesof generators, while structurally different from the fission typegenerator, still operate in a similar manner to produce sodiumpertechnetate using a saline eluent. While the gel generators are nottruly chromatographic, the term ‘eluent’ will be also be used herein todescribe the fluid directed into the generator and the term ‘eluate’will also be used herein to describe the fluid exiting the gel generatorwith the daughter nuclide.

FIG. 2 depicts an activity decay curve for a Mo-99/Tc-99m generator.FIG. 3 shows how the available activity decays over time until reachinga point where the generator is not useful. FIG. 3 also depicts the decaycurve for Tc-99m in a Mo-99/Tc-99m generator after serial elutions ofthe Tc99m isotope ions. Whereas line A depicts the overall decay of theparent nuclide, Mo-99, lines B-D depict the grow-in of the daughternuclide, Tc-99m, up to a near maximum at which time the daughter nuclideis eluted so that there is none left in the column of the generator. Theparent nuclide will continue to decay into the daughter nuclide so theincrease in the available activity of the daughter nuclide is shown overtime. Equation 1 is the equilibrium equation that describes thetheoretical Tc-99m activity (A₂) present in the generator at any time(t) after the previous elution when one knows the Mo-99 activity A⁰ ₁present at the time of the previous elution.

$\begin{matrix}{A_{2} = {{\frac{0.86\lambda_{2}}{\lambda_{2} - \lambda_{1}}{A_{1}^{0}\left( {^{{- \lambda_{1}}t} - ^{{- \lambda_{2}}t}} \right)}} + {A_{2}^{0}^{{- \lambda_{2}}t}}}} & {{Eq}.\mspace{14mu} (1)}\end{matrix}$

Where λ₁ is the decay constant for Mo-99 and λ₂ is the decay constantfor Tc-99m. The present invention links the demand for activity with thecalculated availability of activity for each of the generators.

FIG. 4 depicts a multiple generator elution system 200 of the presentinvention.

Multiple generator elution system 200 incorporates a plurality ofgenerators 110. The generators 110 are desirably connected to a manifold(not shown) that includes valves and conduits so that individual ones ofthe valves are in selectable fluid communication with correspondingindividual ones of the generators. Desirably, the manifold is connectedto a low pressure, or vacuum source, for pulling the eluents throughsystem 300. The manifold directs the generator eluate output to aconcentration column 212. An eluent is directed from a first eluentsource 214 to selected ones of the generators 110 and the resultingeluate from the selected generators is all directed to column 212.Concentration column 212 traps the daughter nuclide from the generatorstherein. A second eluent from a second eluent source 216 is directedthrough concentration column 212 to elute the daughter nuclide into acollection vial 218. The generators 110, column 212, eluent sources 214and 216 and collection vial are desirably placed within the cavity 224of a radiation-shielding hot cell 222 so as to limit exposure of theoperators.

System 200 includes a control system 226 and receiving unit 228.Receiving unit 228 and control system 226 may be provided as part of asingle computer system. Receiving unit 228 receives both supply data anddemand data, which control system 226 can use to generate the elutionschedule for the generators 110 as will be described for FIGS. 9-12. Thesupply data allows calculation of the amount of activity available fromeach of generators 110, based on the calibration data, including theknown starting activity and date, the time and date of when thegenerator was available for use, and the time and date of the firstelution off set. The demand data relates to the amount of activityrequired and when. The demand data may be automatically inputted intothe receiving unit 328 from an ERP module 231, such as SAP or Slimline,or it may be entered in manually into receiving unit 228. Control system226 desirably calculates the elution schedule by determining whichgenerators will be eluted and when so as to match the demand data to theavailable activity so as to maximize the eluted daughter nuclide withthe minimum amount of waste. Control system 226 will then desirablydownload instructions to an actuation system 235 located within hot cell222 for conducting the elutions. The present invention furthercontemplates that control system 226 may be alternatively providedwithin hotcell 222 either separately from actuation system 235 or as aunitary computerized system performing the functions for both.

By way of illustration and not of limitation, in this configuration, thegenerators 110 are Mo99/Tc99m generator (titanium [99Mo] molybdate) gelgenerators. The first eluent source 214 desirably provides a weak acidas the first eluent for eluting the daughter nuclide Tc-99m from thegenerators, although highly pure water, such as sterile water forinjection may also be used to elute the gel generator. Concentrationcolumn 212 includes an alumina sorbent to capture the pertechnate in theeluate from generators 110. Second eluent source 216 provides saline foreluting the sodium pertechnate from column 212 and collection incollection vial 218. The sodium pertechnate may then be used with coldkits for labeling a radiotracer.

With the present invention, any combination of generators may be elutedand the activity from the eluted generators collected in column 212. Thefinal radioactivity concentration is determined by the elution of theconcentration column 212, which can be eluted in a very small volume.Additionally, because the activity can be collected from multiplegenerators and concentrated, the generators may be used continuouslyuntil expiry.

Referring now to FIG. 5, an alternate presentation multiple generatorelution system 200 is shown. In FIG. 5, five gel generators 110 a-e areshown connected with a valve manifold 250. Manifold 250 is desirablybased on the linearly-arranged stopcock manifold used in FASTlab™cassettes, sold by GE Healthcare, Liege, BE. Manifold 250 includessixteen 3way/3position stopcocks valves, 1-17. Each of valves 1-17include three open ports opening to adjacent manifold valves and to arespective luer located therebetween. Each valve includes a rotatablestopcock which puts any two of the three associated ports in fluidcommunication with each other while fluidically isolating the thirdport. The present invention further contemplates that the stopcock couldinclude a T-shaped internal passageway therein so as to also allow allthree ports to be placed in fluid communication across the valve, butsuch an embodiment would provide dead spaces which could requireadditional rinsing so as to prevent the occurrence of contaminationbetween successive fluid flows. Manifold 250 further includes, atopposing ends thereof, first and second socket connectors 18 and 19,each defining vacuum ports 18 a and 19 a, respectively. Manifold 250 andthe stopcocks of valves 1-17, as well as the conduits described below,are desirably formed from a polymeric material, e.g. PP, PE,Polysulfone, Ultem, or Peek. As will be shown in FIG. 8, the manifolddesirably includes twenty-five 3way/3position stopcocks valves, althoughthe actual number of valves is scaleable to meet the needs of the user.Unused valves may simply have their luer connection capped by a luerfitting and their stopcocks providing fluid communication for flowbetween adjacent valves.

Each of the connections at the valves described herein are made at theport defined by its luer connector. As shown in FIG. 5, valve 1 supportsa filtered vent 251 at its luer connection. Valve 2 is connected tofirst eluent source 214 by an elongate conduit 252. First eluent source214 provides the eluent for eluting the daughter nuclide from generators110 a-e. First eluent source 214 desirably is also connected in fluidcommunication with a filtered vent 233 to assist the outflow of theeluent through conduit 252 towards valve 2. Valve 3 is connected by anelongate conduit 254 to a second manifold 256 providing open connectionto the eluent channels 118 of generators 110 a-e. That is, the presentinvention desirably provides a single source of eluent for eluting eachof the generators, although the present invention also contemplates thateach generator may have its own source of eluent as shown in FIG. 1. Theeluate channels 120 of generators 110 a-e are connected back to manifold250 by elongate conduit 260 a-e, respectively. Conduits 260 a-e extendbetween the respective eluate channels 120 of generators 110 a-e tovalves 4-8, respectively.

Valve 9 is connected by elongate conduit 262 to an input port ofconcentration column 212 so that eluate from the generators may bedirected to column 212. Valve 10 is connected to second eluent source216 by an elongate conduit 264. Second eluent source 216 provides theeluent to elute the daughter nuclide from column 212. Second eluentsource 216 desirably is also connected in fluid communication to afiltered vent 263 to assist outflow of the second eluent through conduit262 towards valve 9. Valves 11 and 12 are capped by a luer fitting andtheir stopcocks oriented to provide fluid flow there through betweenvalves 10 and 13. Valve 13 is connected by elongate conduit 266 to aninput port 268 of collection vial 218 so as to be able to direct aproduct fluid therein. Valve 14 is connected by elongate conduit 270 toan input port 272 of a waste vial 219. Valve 15 is connected to theoutput port of column 212, such that column 212 desirably connectsdirectly to valve 15. Valve 16 is connected by elongate conduit 274 toan outlet port 275 of waste vial 215. Valve 17 is connected by elongateconduit 276 to an outlet port 278 of collection vial 218.

A sample elution will now be described. An elution schedule has beencalculated that requires eluting the activity from generators 110 a and110 c. By application of a vacuum (ie, a sufficient low pressure) atport 19 a, the first eluent will be drawn from first source 214. Valves1-17 are set so that the first eluent flows through valves 2 and 3 andconduit 254 into manifold 256. First, valves 5-8 are set to allow foreluate flow from generator 110 a to flow through conduit 260 a throughto valve 9. Valve 9 directs the eluate flow through conduit 262 to theinput port of column 212. From column 212 the eluate will be drawnthrough valve 15 to valve 14 and into waste vial 219. The volume ofwaste vial 219 will be sufficient to collect all of the liquid thusdelivered from column 212. The stopcock of valve 4 is then rotated toisolate generator 110 a and the stopcock of valve 6 is rotated so thatthe first eluent will be drawn from second manifold 256 into generator110 c. The eluate from generator 110 c is then directed through valves6-8 to valve 9. Valve 9 directs the eluate flow through conduit 262 tothe input port of column 212. From column 212 the eluate will be drawnthrough valve 15 to valve 14 and into waste vial 219. The daughternuclides from generator 110 a and 110 c have thus been collected inconcentration column 212.

To elute the daughter nuclide from column 212, valve 10 will be set todirect, under suction at port 19 a, the second eluent from source 264through conduit 264 and towards valve 9. The second eluent is drawnthrough conduit 262 through the input port of column 212 and throughcolumn 212. Upon exiting column 212 into valve 15, the column 212 eluatewill contain the daughter nuclide for dispensement into collection vial218. This eluate will be directed to valve 13 and through conduit 266into vial 218, the suction from port 19 a being applied through valve 17and conduit 276. Vial 218 may then be either removed or drawn from toprovide the daughter nuclide for further processing by the pharmacist.Subsequent dispensements from the generators may thus be directed intothe same collection vial or otherwise combined with unused eluate from aprevious dispensement, as control system 226 has included any leftoveractivity in its calculations for dispensing from generators 110 a-e inorder to meet the requirements of the demand data. Manifold 250 isdesirably formed to be attached to an actuation system 235 which engagesand sets the orientation of the stopcocks of the valves and provides thelow-pressure suction, or vacuum, for drawing fluids through the manifoldand into the vials. Actuation system 235 includes rotatable arms whichengage each of the stopcocks of valves 1-17 and can position each in adesired orientation throughout elution operations. The actuation system235 also includes a pair of spigots, each of which engages one of ports18 a and 19 a in fluid-tight connection to provide a source of lowpressure, or vacuum, to manifold 250 in accordance with the presentinvention. Desirably, manifold 250 is attachable to a FASTLab™ (sold byGE Healthcare, Liege, BE) synthesis device which has been programmed tooperate the valves and apply the vacuum. As the FASTlab synthesizer isalready designed to operate in a hot cell environment, it is ideallysuited as the actuation device for system 200. Actuation system 235 isdirected to act by control system 226 according to the calculatedelution schedule.

FIGS. 6 and 7 depict a multiple generator elution system 300 foralumna-based Mo-99 generators 110. Multiple generator elution system 300incorporates a plurality of generators 110. In this embodiment, thegenerators 110 are Mo99/Tc99m alumina generators (ie, incorporatealumina in the generator's column). The generators 110 are desirablyconnected to a manifold (not shown) that includes valves and conduits sothat individual ones of the valves are in selectable fluid communicationwith corresponding individual ones of the generators. The manifolddirects the generator eluate output to a cation column 315. Thegenerator eluate flows through the cation column 315 and then into aconcentration column 312. Desirably, the manifold is connected to avacuum source for pulling the eluents through system 300. The cationcolumn is not used for trapping the daughter nuclide but contains anappropriate media for removing competing ions which adversely interferewith the concentration column. Thus, in system 300 an eluent is directedfrom a first eluent source 314 to selected ones of the generators 110and the resulting eluate from the selected generators is all directedthrough column 315 and to column 312. Concentration column 312 traps thedaughter nuclide from the generators therein. A second eluent from asecond eluent source 316 is directed through concentration column 312 toelute the daughter nuclide into a collection vial 318. The generators110, column 312, eluent sources 314 and 316 and collection vial aredesirably placed within the cavity 324 of a radiation-shielding hot cell322 so as to limit exposure of the operators.

System 300 includes a control system 326 and receiving unit 328.Receiving unit 328 and control system 326 may be provided as part of asingle computer system. Receiving unit 328 receives both supply data anddemand data, which control system 226 can use to generate the elutionschedule for the generators 110 as will be described for FIGS. 9 and 10.The supply data allows calculation of the amount of activity availablefrom each of generators 110, based on the calibration data, includingthe known starting activity and date, the time and date of when thegenerator was available for use, and the time and date of the firstelution off set. The demand data relates to the amount of activityrequired and when. The demand data may be automatically inputted intothe receiving unit 328 from an electronic ERP module 331, such as SAP orSlimline, or it may be entered in manually into receiving unit 328 by anoperator. Control system 326 desirably calculates the elution scheduleby determining which generators will be eluted and when so as to matchthe demand data to the available activity so as to maximize the eluteddaughter nuclide with the minimum amount of waste. Control system 326will then desirably download instructions to an actuation system 335located within hot cell 322 for conducting the elutions. The presentinvention further contemplates that control system 326 may bealternatively provided within hotcell 322 either separately fromactuation system 335 or as a unitary computerized system performing thefunctions for both.

In this configuration, first eluent source 314 desirably provides anacid salt or weak acid, typically saline, as the first eluent foreluting the daughter nuclide Tc-99m from the generators. As the firsteluent is saline, cation column 315 is used first to remove the sodiumion so as to allow concentration on the concentration column 312.Concentration column 312 includes an alumina sorbent to capture thepertechnate in the eluate from generators 110. Second eluent source 316provides saline for eluting the sodium pertechnate from column 312 andcollection in collection vial 318. The sodium pertechnate may then beused with cold kits for labeling a radiotracer.

With the present invention, any combination of generators may be elutedand the activity from the eluted generators passed through column 315and collected in column 312. The two column method allows generatorsbased on fission Mo-99 and alumina technology to take advantage of theefficiencies of the concentrator system of the present invention. Thefinal radioactivity concentration is determined by the elution of theconcentration column 312, which can be eluted in a very small volume.Additionally, because the activity can be collected from multiplegenerators and concentrated, the generators may be used continuouslyuntil expiry.

Referring now to FIG. 7, an alternate presentation of multiple generatorelution system 300 is shown. In FIG. 7, five gel generators 110 a-e areshown connected with a valve manifold 350. Manifold 350 is desirablybased on the linearly-arranged stopcock manifold used in FASTlab™cassettes, sold by GE Healthcare, Liege, BE. Manifold 350 includessixteen 3way/3position stopcocks valves, 1-17. Each of valves 1-17include three open ports opening to adjacent manifold valves and to arespective luer located thereon, the luer port located between theopposed other ports. Each valve includes a rotatable stopcock which putsany two of the three associated ports in fluid communication with eachother while fluidically isolating the third port. The present inventionfurther contemplates that the stopcock could include a T-shaped internalpassageway therein so as to also allow all three ports to be placed influid communication across the valve, but such an embodiment wouldprovide dead spaces which could require additional rinsing so as toprevent the occurrence of contamination between successive fluid flows.Manifold 350 further includes, at opposing ends thereof, first andsecond socket connectors 18 and 19, each defining vacuum ports 18 a and19 a, respectively. Manifold 350 and the stopcocks of valves 1-17, aswell as the conduits described below, are desirably formed from apolymeric material, e.g. PP, PE, Polysulfone, Ultem, or Peek. As will beshown in FIG. 8, the manifold desirably includes twenty-five3way/3position stopcocks valves, although the actual number of valves isscaleable to meet the needs of the user. Unused valves may simply havetheir luer connection capped by a luer fitting and their stopcocksproviding fluid communication for flow between adjacent valves.

Each of the connections at the valves described herein are made at theluer port defined by its luer connector. As shown in FIG. 8, valve 1supports a filtered vent 351 at its luer connection. Valve 2 isconnected to first eluent source 314 by an elongate conduit 352. Firsteluent source 314 provides the eluent for eluting the daughter nuclidefrom generators 110 a-e. First eluent source 314 desirably is alsoconnected in fluid communication with a filtered vent 333 to assist theoutflow of the eluent through conduit 352 towards valve 2. Valve 3 isconnected by an elongate conduit 354 to a second manifold 356 providingopen connection to the eluent channels 118 of generators 110 a-e. Thatis, the present invention desirably provides a single source of eluentfor eluting each of the generators, although the present invention alsocontemplates that each generator may have its own source of eluent asshown in FIG. 1. The eluate channels 120 of generators 110 a-e areconnected back to manifold 350 by elongate conduit 360 a-e,respectively. Conduits 360 a-e extend between the respective eluatechannels 120 of generators 110 a-e to valves 4-8, respectively.

Valve 9 is connected by elongate conduit 362 to an input port of acation column 315. Cation column 315 serves to remove competing ionsfrom the eluate from the generators prior to concentration. Valve 10 isconnected to second eluent source 316 by an elongate conduit 364. Secondeluent source 316 provides the eluent to elute the daughter nuclide fromcolumn 312. Second eluent source 316 desirably is also connected influid communication to a filtered vent 363 to assist outflow of thesecond eluent through conduit 362 towards valve 9. Valve 11 is connectedto the output port of cation column 315. Valve 12 is connected byelongate conduit 365 to an input port of concentration column 312.

Valve 13 is connected by elongate conduit 370 to an input port 372 of awaste vial 319. Valve 14 is connected by elongate conduit 366 to aninput port 368 of collection vial 318 so as to be able to direct aproduct fluid therein. Valve 15 is connected to the output port ofcolumn 312, such that column 312 desirably connects directly to valve15. Valve 16 is connected by elongate conduit 374 to an outlet port 375of waste vial 315. Valve 17 is connected by elongate conduit 376 to anoutlet port 378 of collection vial 318.

A sample elution will now be described. The elution schedule has beencalculated that requires eluting the activity from generators 110 a and110 c. By application of a vacuum (ie, a sufficient low pressure) atport 19 a, the first eluent will be drawn from first source 314. Valves1-17 are set so that the first eluent flows through valves 2 and 3 andconduit 354 into manifold 356. First, valves 5-8 are set to allow foreluate flow from generator 110 a to flow through conduit 360 a throughto valve 9. Valve 9 directs the eluate flow through conduit 362 to theinput port of cation column 315. From column 315 the eluate will bedrawn through valve 12 and into elongate conduit 265 into the inlet portfor concentration column 312. Waste material will continue to be drawnthrough column 312 through valve 15 down to valve 13 and into waste vial319. The volume of waste vial 319 will be sufficient to collect all ofthe liquid thus delivered from column 315. The stopcock of valve 4 isthen rotated to isolate generator 110 a and the stopcock of valve 6 isrotated so that the first eluent will be drawn from second manifold 356into generator 110 c. The eluate from generator 110 c is then directedthrough valves 6-8 to valve 9. Valve 9 directs the eluate flow throughconduit 362 to the input port of column 315. From column 315 the eluatewill be drawn through valve 12 and into elongate conduit 265 into theinlet port for concentration column 312. Waste material will continue tobe drawn through column 312 through valve 15 down to valve 13 and intowaste vial 319. The daughter nuclides from generator 110 a and 110 chave thus been collected in concentration column 312.

To elute the daughter nuclide from column 312, valve 10 will be set todirect, under suction at port 19 a, the second eluent from source 316through conduit 364 and towards valve 12. The second eluent is drawnthrough conduit 365 through the input port of column 312 and throughcolumn 312. Upon exiting column 312 into valve 115, the column 312eluate will contain the daughter nuclide for dispensement intocollection vial 318. This eluate will be directed to valve 14 andthrough conduit 366 into vial 318, the suction from port 19 a beingapplied through valve 17 and conduit 376. Vial 318 may then be eitherremoved or drawn from to provide the daughter nuclide for furtherprocessing by a pharmacist or technician. Subsequent dispensements fromthe generators may thus be directed into the same collection vial orotherwise combined with unused eluate from a previous dispensement, ascontrol system 326 has included any leftover activity in itscalculations for dispensing from generators 110 a-e in order to meet therequirements of the demand data.

Manifold 350 is formed to be attached to actuation system 335 whichengages and sets the orientation of the stopcocks of the valves andprovides the low-pressure suction, or vacuum, for drawing fluids throughthe manifold and into the vials. Actuation system 335 includes rotatablearms which engage each of the stopcocks of valves 1-17 and can positioneach in a desired orientation throughout elution operations. Theactuation system 335 also includes a pair of spigots, each of whichengages one of ports 18 a and 19 a in fluid-tight connection and toprovide a source of low pressure, or vacuum, to manifold 350 inaccordance with the present invention. Desirably, manifold 250 isattachable to a FASTLab™ (sold by GE Healthcare, Liege, BE) synthesisdevice which has been programmed to operate the valves and apply thevacuum. As the FASTlab synthesizer is already designed to operate in ahot cell environment, it is ideally suited as the actuation device forsystem 300. Actuation system 335 is directed to act by control system326 according to the calculated elution schedule.

Referring now to FIG. 8, an elution cassette 400 for use with a multiplegenerator elution system is shown. In FIG. 8, four alumina generators110 a-d for producing Tc-99m from decaying Mo-99 are shown connectedwith a valve manifold 450. Cassette 400 includes a case 402 with aplanar front wall 404 bounded by a perimetrical wall 406 defining a casecavity 408. Cassette 400 supports an elongate manifold 450 in cavity 408adjacent to a bottom wall 406 a. Manifold 450 is desirably based on thelinearly-arranged stopcock manifold used in FASTlab™ cassettes, sold byGE Healthcare, Liege, BE. Manifold 450 includes twenty five3way/3position stopcocks valves, 1′-25′. Each of valves 1′-25′ includethree open ports opening to adjacent manifold valves and to a respectiveluer located thereon, the luer port located between the opposed otherports. Each valve includes a rotatable stopcock which puts any two ofthe three associated ports in fluid communication with each other whilefluidically isolating the third port. The present invention furthercontemplates that the stopcock could include a T-shaped internalpassageway therein so as to also allow all three ports to be placed influid communication across the valve, but such an embodiment wouldprovide dead spaces which could require additional rinsing so as toprevent the occurrence of contamination between successive fluid flowsand loss of fluid trapped in deadspaces therein. Manifold 450 furtherincludes, at opposing ends thereof, first and second socket connectors26 and 27, each defining vacuum ports 26 a and 27 a, respectively.Manifold 450 and the stopcocks of valves 1′-25′, as well as the conduitconnectors described below, are desirably formed from a polymericmaterial, e.g. PP, PE, Polysulfone, Ultem, or Peek. As shown in FIG. 8,the manifold includes twenty-five 3way/3position stopcocks valves,although the actual number of valves is scaleable to meet the needs ofthe user. Unused valves may simply have their luer connection capped bya luer fitting and their stopcocks providing fluid communication forflow between adjacent valves.

Cassette 400 is a variant of a pre-assembled synthesis cassette designedto be adaptable for synthesizing clinical batches of differentradiopharmaceuticals with minimal customer installation and connections.Cassette 400 is desirably provided in kit form with all of the conduittubings and supported connectors and filters to be connected to thegenerators, vials, and eluent source or sources for eluting a nuclideaccording to the present invention. Desirably, cassette 400 is providedto users with each connection of the conduits to the luers of its valvesalready made, so that only the free ends need to be mated with theappropriate component. The cassette so provided may be assembled andpackaged in a sterile condition such that if opened in an appropriatelyclean environment will maintain an appropriate level of sterility forpharmaceutical operations.

Each of the connections at the valves described herein are made at theluer port defined by its luer connector. As shown in FIG. 8, valve 3′supports a filtered vent 451 at its luer connection. Valve 4′ isconnected to rinse fluid source 415 by an elongate conduit 452. Rinsefluid source 415 provides a rinse fluid for rinsing manifold 250 betweenelution runs or as desired. Rinse fluid source 415 desirably is alsoconnected in fluid communication with a filtered vent 433 to assist theoutflow of the eluent through conduit 452 towards valve 4′. That is,while the present invention contemplates that cassette 400 can provide asingle source of eluent for eluting each of the generators as describedin FIGS. 5 and 8, in the embodiment of FIG. 8, the present inventionincludes each generator having its own source of eluent, provided in aneluent vial 130, as shown in FIG. 1. Providing each generator with itsown eluent source 130 may be desirable so as to prevent the risk ofover-dilution of the eluate volume from a common reservoir.Additionally, by providing each generator with its own attached elutionsource, more of the manifold valves 5′-14′ will be available forconnection to a generator. The air vent on the manifold is used to bleedoff excess or unused vacuum. The eluate channels 120 of generators 110a-d are connected back to manifold 450 by elongate conduit 460 a-d,respectively. Conduits 460 a-d extend between the respective eluatechannels 120 of generators 110 a-d to valves 15′-18′, respectively.

Valves 5′-14′ are each capped by a luer fitting which seals the luerport for each valve. Valves 5′-14′ are available for scaling up cassette400 to accommodate additional generators, should a user so desire.

Valve 19′ is connected by elongate conduit 462 to an input port of acation column 415. Cation column 415 serves to remove competing ionsfrom the eluate from the generators prior to concentration. Valve 20′ isconnected to the output port of cation column 415. Valve 21′ isconnected by elongate conduit 465 to an input port of concentrationcolumn 412. Valve 22′ is connected to second eluent source 416 by anelongate conduit 464. Second eluent source 416 provides the eluent toelute the daughter nuclide from concentration column 412. Second eluentsource 416 desirably is also connected in fluid communication to afiltered vent 463 to assist outflow of the second eluent through conduit462 towards valve 22′. Valve 24′ is connected to the output port ofcolumn 412, such that column 412 desirably connects directly to valve24′.

Now the connections to the waste and collection vials will be described.Valve 23′ is connected by elongate conduit 470 to an input port 472 of awaste vial 419. Valve 25′ is connected by elongate conduit 466 to aninput port 468 of collection vial 418. Valve 1′ is connected by elongateconduit 476 to an outlet port 478 of collection vial 418. Valve 2′ isconnected by elongate conduit 474 to an outlet port 475 of waste vial415.

A sample elution will now be described. The elution schedule has beencalculated that requires eluting the activity from generators 110 b and110 d. By application of a vacuum (ie, a sufficient low pressure) atport 26 a, the first eluent will be drawn from first source vial 130 forgenerator 110 b. Valves 1′-25′ are set so that the first eluent flowsthrough generator 110 b, through conduit 460 b to valve 16′ and onthrough to valve 19′. Valve 19′ directs the eluate flow through conduit462 to the input port of cation column 415. From column 415 the eluatewill be drawn through valve 21′ and into elongate conduit 465 into theinlet port for concentration column 412. Waste material will continue tobe drawn through column 412 through valve 24′ down to valve 23′ and intowaste vial 419. The volume of waste vial 419 will be sufficient tocollect all of the liquid thus delivered from column 412.

The stopcock of valve 16′ is then rotated to isolate generator 110 b andthe stopcock of valve 18′ is rotated so that the first eluent will bedrawn from the vial 130 connected to generator 110 d. The eluate fromgenerator 110 d is then directed through conduit 460 d to valve 18′ andthen on to valve 19′. Valve 19′ directs the eluate flow through conduit462 to the input port of column 415. From column 415 the eluate will bedrawn through valve 21′ and into elongate conduit 465 into the inletport for concentration column 412. Waste material will continue to bedrawn through column 412 through valve 24′ down to valve 23′ and intowaste vial 419. The daughter nuclides from generator 110 b and 110 dhave thus been collected in concentration column 412.

To elute the daughter nuclide from column 412, valve 22′ will be set todirect, under suction at port 26 a, the second eluent from source 416through conduit 464 and valve 22′ and towards valve 21′. The secondeluent is drawn through conduit 465 through the input port of column 412and through column 412. Upon exiting column 412 into valve 24′, thecolumn 412 eluate will contain the daughter nuclide for dispensementinto collection vial 418. This eluate will be directed to valve 25′ andthrough conduit 466 into vial 418, the suction from port 26 a beingapplied through valve 1′ and conduit 476. Vial 418 may then be eitherremoved or drawn from to provide the daughter nuclide for furtherprocessing by the pharmacist. Subsequent dispensements from thegenerators may thus be directed into the same collection vial orotherwise combined with unused eluate from a previous dispensement, asthe control system of the present invention has included any leftoveractivity in its calculations for dispensing from generators 110 a-d inorder to meet the requirements of the demand data.

Cassette 400 is formed to be attached to an actuation system whichengages and sets the orientation of the stopcocks of the valves andprovides the low-pressure suction, or vacuum, for drawing fluids throughthe manifold and into the vials. The actuation system includes rotatablearms which engage each of the stopcocks of valves 1′-25′ and canposition each in a desired orientation throughout elution operations.The actuation system also includes a pair of spigots, each of whichengages one of ports 26 a and 27 a in fluid-tight connection and toprovide a source of low pressure, or vacuum, to manifold 450 inaccordance with the present invention. Desirably, manifold 450 isattachable to a FASTLab™ (sold by GE Healthcare, Liege, BE) synthesisdevice which has been programmed to operate the valves and apply thevacuum. As the FASTlab synthesizer is already designed to operate in ahot cell environment, it is ideally suited as the actuation device forcassette 400, receiving its actuation instructions from a control systemto operate according to the calculated elution schedule.

For all embodiments of the cassette and manifold systems of the presentinvention, including those detailed in FIGS. 5, 7, and 8, the cassetteor manifold is desirably attachable to a FASTlab device. All liquidtransfers are performed by the applied vacuum (or low pressure). Allconnections to the manifold cassette are contemplated to be via standardluer locks. The conduits used to connect to the generator are desirablysilicon tubing terminated with a septum to allow penetration by theneedles 125 a and 129 a at the respective port on the generator 110. Inthe event an eluent vial 130 is attached to a generator, a standardconnection may be used. Thus the generators do not need to be modifiedto work with the present invention.

Additionally for all embodiments, an external source of rinse fluid,such as water for injection (WFI), may also be connected to the manifoldfor cleaning and rinsing proposes. When eluting a gel generator, the WFIsource may be connected to each generator to also act as a first eluent.As more particularly described for FIG. 8, the present inventioncontemplates that first eluent can be from a reservoir or a pre measuredcontainer or “elution vial” individually connected to each generator. Apre-measured source is desirable so as to prevent over dilution of theeluate volume and to free up an additional manifold valve for connectionto a generator. The air vent on the manifold is used to bleed off excessor unused vacuum.

The present invention further contemplates that for some embodiments,depending on the required elution chemistry, the first source of eluentthat is connected directly to the manifold (as described for FIGS. 5 and7) may be used to elute both the generators and the concentrationcolumn, thus obviating the need for a second source of eluent to beconnected to the manifold. For example, if system 300 of FIG. 7 employsalumina generators and an alumina concentration column, the presentinvention contemplates that first source of eluent may provide salinethat is used both for eluting the generators and for eluting theconcentration column.

The cation column is used to remove competing ions, such as chloride,from the eluate. In some embodiments, the pertechnetate ions flowthrough the cation column and on to the acidified alumina column whereit is captured (concentrated). The liquid is allowed to flow through thecolumn and into the waste collection vessel for future disposal. Theacidified alumina column (as stated above) is used to capture andconcentrate the pertechnetate (^(99m)Tc). While the pertechnetate isbeing captured on the alumina column, the liquid (essentially water) isremoved from the bottom of the column by vacuum and collected in thewaste vessel. Once the concentration step is completed the aluminacolumn is desirably eluted with a small volume of saline to remove thepertechnetate as sodium pertechnetate [Na^(99m)TcO⁴⁻], basically inexactly the same way as current fission generators and collected in theproduct collection vial.

With reference to FIG. 9, the present invention uses demand data andsupply data to determine and execute the most efficiency utilization ofa set of parent-daughter generators in a radio-pharmacy operation. Thesupply data allows the automated calculation of the amount of availableactivity (of the daughter nuclide) at any given time. Generators aresold with known amounts of activity. The supply data can be obtainedfrom a generator barcode or manual data entry. The demand data is theamount of activity required at specific times to meet customer orders.The data can come from either an ERP software system, for example SAP orSlimline (or equivalent) via an electronic transfer, or by manual entry.Typically, in a radio-pharmacy environment, customer orders aresegregated into delivery runs, scheduled at certain times of the day.

The present invention compares the demand activity requirements with theavailable activity at any given time. Additionally, the system willattempt to configure the generator elution plan to deliver a best-fitsolution representing the best efficiency for eluting from the givengenerators. Once the best fit solution has been calculated, the operatorhas several options: a) Execute the elution plan determined by thesystem, b) reconfigure the elution plan manually—letting the systemcalculate and display the effect to the operator, or c) model ‘what-ifscenarios’ by inputting certain demand requirements and/or supply dataand reviewing the calculated elution schedule determined by the systemunder the entered constraints.

The present invention, upon confirmation from the operator thecalculated elution plan is acceptable, sends the data to the actuationsystem to elute the selected generators according the elution schedule.The eluates from the selected generators are all passed through thecassette to concentrate, for example, Tc-99m, onto an alumina column.Once all the generator elutions are complete, the alumina column iseluted in the required volume of eluent, eg, saline, (typically 5-6 mL).Once this operation is completed, the control system updates theactivity data, re-calculates the grow-in and updates the elutionschedule with any required changes.

Generally, an ERP system is an integrated computer-based applicationused to manage internal and external resources, including tangibleassets, financial resources, materials, and human resources. Its purposeis to facilitate the flow of information between all business functionsinside the boundaries of the organization and manage the connections tooutside stakeholders. Built on a centralized database and normallyutilizing a common computing platform, ERP systems consolidate allbusiness operations into a uniform and enterprise-wide systemenvironment. An ERP system can either reside on a centralized server orbe distributed across modular hardware and software units that provide“services” and communicate on a local area network. The distributeddesign allows a business to assemble modules from different vendorswithout the need for the placement of multiple copies of complex andexpensive computer systems in areas which will not use their fullcapacity.

The method of the present invention thus includes an inputting step 610where the supply data for each of the generators is inputted into areceiving unit of the elution system. The method then includes a secondstep 620 of inputting into the receiving unit the demand data of whatactivity is required and when from the multiple generators. This isfollowed by a calculating and selecting step 630 where the optimumelution schedule for each of the multiple generators is determinedaccording to the inputted supply data and the inputted demand data. Thecalculating and selecting step 630 desirably compares current demand ofactivity, future demand for activity, and the available activity fromthe generators both presently and at subsequent demand points, orelution times, and selects which generators will be eluted and when soas to minimize the waste of daughter nuclide produced by the generatorsin meeting the demand data. Then, there is an eluting step 670 in whichthe daughter nuclide is eluted from the selected generators.

Step 610 further includes the steps of inputting calibration data foreach generator, 612, typically the activity and date for each generator,inputting the time and date that the generator is available, 614, andinputting the time and date that the first elution is off-set from areference time. Steps 612, 614, 616 may be performed manually bymanually entering into the receiving unit the information from each ofthese steps, such information generally being provided with eachgenerator. Alternatively, steps 612, 614, and 616 may be performedelectronically, or automatically, by scanning such information from abar code pertaining to each generator. Likewise, step 620 may beperformed either manually or electronically, with the demand datagenerally being supplied by an ERP system. For manually performing step620, an operator will take the demand data information and enter it intothe receiving unit. Desirably, when the demand data is manually entered,the receiving unit or control system will compiling the information intothe demand data set, although the operator may also perform thecompilation prior to entering the aggregate demand data. Alternatively,the ERP system may be electronically communicating with the receivingunit so that the individual orders are automatically entered into thesystem and the elution schedule calculated.

The present invention further contemplates that step 610 can include thestep of inputting known data constants, 618. Step 618 can provide forthe consideration of such data constants in the step 630. The dataconstants desirably include the parent nuclide half-life and decayequation, the daughter nuclide half life and decay equation, the elutionyield efficiency, the fraction of the elution available the parentnuclide decay, the equilibrium equation for the parent-daughteractivity, and the expiration time for the generator.

Step 630 includes the step of calculating 632 and displaying 634 theavailable activity for each generator, desirably in fixed intervals suchas thirty minutes. Desirably, the calculating step 632 employs Equation(1) and the displaying step 634 displays the activity in each generatorat the calculated intervals. Moreover, step 630 may include the step ofperforming a Generalized Reduced Gradient Algorithm analysis of thedemand data and the activity levels of the plurality of generators todetermine the optimum elution schedule for minimizing waste.Alternatively, step 630 is contemplated to run simulations of variouselution schedules from the plurality of generators and selecting theelution schedule resulting in the lowest amount of waste of the daughternuclide upon meeting the demand data. Additionally, the method desirablyincludes the step 638 of displaying the demand data over the sameintervals as the supply data. Step 630 desirably further comprises thestep of calculating the best fit elution profile, or schedule, 638, forselecting which of the available generators will be eluted at a giventime to meet the demand data in the most efficient way possible, thusmaximizing the useful life of each generator and minimizing waste. Themethod may then include the step of providing the elution schedule tothe operator, 640.

Desirably, the display of the elution schedule is provided on agraphic-user interface (GUI) and the method includes the steps ofoffering the operator the option of overriding the calculated optimizedelution schedule, 642, by instead scheduling different generators forelution at a given time. If the operator declines to override thesystem, the method will then progress to the step of sending the elutioninstructions to the actuation system, 660. If the operator chooses tooverride the elution instructions from step 638, the method furtherincludes the step of the operator manually entering a modification tothe elution schedule, 644. Step 644 allows the operator to select a whenparticular generators will be eluted. The method then includes the stepof recalculating the elution schedule, 646, and displaying both theupdated activity availability over time for each generator as well asthe scheduled time of elution from each of the generators, 648. Step 646desirably employs the same algorithm as step 630 in determining theoptimum elution schedule, given any additional operator constraints. Themethod then includes the step of prompting the operator to accept theupdated elution schedule 650. If the operator accepts the updatedelution schedule, the elution schedule will be set and the controlsystem will provide the appropriate instructions to the actuation systemfor eluting from the generators, step 660. If the operator does notaccept the updated elution schedule, the method will repeat steps 644,646, and 648 until the operator does accept the elution schedule. Oncethe updated elution schedule is satisfactory to the operator, the methodwill proceed to step 660.

After step 660, the actuation system will perform step 670 and elute thegenerators according to the elution schedule. Steps 642, 644, 646, 648,and 650 provide the option of an ‘operator-in-the-loop’ to oversee andmanage the elution from the generators and allow the operator tooverride the calculated schedule. In any event, the present invention isable to operate without the need for operator intervention and can thusperform the scheduled elutions automatically without operator input oncethe schedule, thereby freeing the operator to tend to other pharmacyduties. However, it is deemed desirable to provide the operator at somepoint in the cycle so as to accept the elution schedule.

After the eluting step 670, the method can include the step ofconfirming that the selected generators were eluted, 672. Additionally,the method desirably includes the steps of re-calculating the activityin-growth 674, modifying the activity data in step 632 and, ifnecessary, repeating steps 638 et seq. to recalculate the best-fitelution schedule for meeting the demand data.

The present invention further provides a computer program product formanaging the elution from a multiple generator elution system accordingto the present invention. The present invention further provides amultiple generator elution system which includes computer hardware forexecuting the computer program product of the present invention.

The computer program product includes computer usable medium havingcomputer-usable program code for performing the method of the presentinvention. The computer program code includes a computer-usable mediumhaving computer-usable program code that manages a multiple generatorelution system. The computer program product including computer-usableprogram code that receives inputted supply data for a number ofparent-daughter generators and demand data for activity from thegenerators. The computer program further includes computer-usableprogram code that calculates an elution schedule for the generatorsbased on the available activity in the generators and the demand data;as well as computer program code that directs an actuation system of theelution system to elute from selected ones of the generators accordingto the elution schedule.

The computer program product desirably further includes computer programcode for displaying at least one of the supply data, the demand data,the available activity in the generators, and the elution schedule.Additionally, the computer program code that calculates an elutionschedule also includes computer program code for performing aGeneralized Reduced Gradient Algorithm analysis of the demand data andthe activity levels of the plurality of generators to determine theoptimum elution schedule for minimizing waste. Alternatively, thecomputer program code for calculating an elution schedule also includescomputer program code for running simulations of various elutionschedules from the plurality of generators and selecting the elutionschedule resulting in the lowest amount of waste of the daughter nuclideupon meeting the demand data. The computer program product desirablyalso includes computer program code for allowing an operator to overridethe calculated elution schedule by inputting new constraints to thecomputer program product, and computer program code for calculating anew elution schedule based on the new constraints. Moreover, thecomputer program product desirably includes computer program code forstoring the supply data, the demand data, and the elution schedule forfuture retrieval and can serve for purposes of record keeping orsupporting record keeping.

FIG. 10 depicts a screen shot of a graphical user interface (GUI) of thepresent invention for providing supply data information for a multiplegenerator elution system of the present invention. FIG. 10 shows thesupply data input screen 700. Screen 700 provides a Microsoft Excel®screen showing the supply data for the six generators listed in columnA, rows 6-11. Column B, rows 6-11 lists the Reference Time for eachgenerator. Column C, rows 6-11 lists the first elution offset (in hours)for each of the listed generators. Lack of an entry will be treated aszero offset. Column D, rows 6-11 list the starting activity at thereference time for each generator. Column E, rows 6-11 lists when eachgenerator was available for use. As an error check for the data entry,the Reference Time in Column A must be at least twelve hours prior tothe Available for use time in Column E. Column F, rows 6-11 will showany error messages for each generator. Column E, rows 2-3 provides theNet Efficiency, or elution yield efficiency, for the generators,typically about 0.83.

FIG. 11 depicts a screen shot of a GUI of the present invention forproviding the elution schedule calculated for the six generators of FIG.10. FIG. 10 shows an elution management window 800 providing the supplydata, demand data, and elution schedule for a multiple generator elutionsystem. This is the worksheet or best fit result for balancingefficiency with future activity needs based on the demand. While FIG. 11displays a close-up of the relevant information in rows 46 to 69,representing from Jul. 11, 2010 at 10 p.m. to Jul. 12, 2010 at 9:30 am,the information of window 800 continues for the life of the generators,typically two weeks and may be scrolled to. Column A, rows 46 to 69,provides the interval times for which the calculations and dispensingsoccur over the shown time period. The time intervals are given in thirtyminute intervals. Column D, rows 46 to 69 lists the time for whendispensing must occur according to the demand data. The listed timetakes into account the further processing time required post-elution toget the nuclides to the user in the desired state. Thus, for example,Column D shows that elutions will be run on Monday Jul. 12, 2010 at12:00 am, 2:00 am, 4:00 am, and 7:00 am. Scrolling further down thetable to unseen rows will show the demand and other information at latertimes. Column E provides the balance remaining from any previouselutions that were not used, and shows the decay as time goes forward.Columns F, P, Z, AJ, AT, and BD note when elutions are schedule for thegenerators listed in Row 1, Columns G, Q, AA, AK, AU, and BE,respectively. The number ‘1’ is entered into columns F, P, Z, AJ, AT,and BD at the time in which the activity was eluted from the respectivegenerator. As can be seen, for each eluted generator, the next row afterelution shows much less activity, indicating that, post elution,activity grow-in is occurring.

As shown in Column D, row 50, at midnight (row 50) there is a demand for14,350 mCi of activity. The control system has calculated that, in orderto best meet all of the known demand in Column D, generator 1 andgenerator 5 will be eluted to meet this demand, providing an unusedbalance of 27 mCi, which may incorporated into future elutions.Similarly, at the 2:00 am elution (row 54), in order to meet the demandfor 15,931 mCi of activity, 2405.5 mCi of activity will be eluted fromgenerator 2, 2405.5 mCi of activity will be eluted from generator 3, and11,120.5 mCi of activity will be eluted from generator 4, providing anunused balance of 22 mCi. The remaining activity from the previouselution will also be included in this elution, so in some instance thecurrent elutions may not total the listed demand on their own.

An operator may override the provided elution schedule by deleting the‘1’ from the elute column and selecting another generator to elute from.The control system will re-populate the entries in window 800 to showthe new elution schedule as well as the available activity in eachgenerator at each given time, the demand at each elution time, and anybalance in activity that is leftover. The modeling feature of thepresent invention allows, for example, that when a supply shock occurs,the present invention to be particularly useful for evaluating theimpact of “what if” scenarios, and ultimately delivering the most dosesfor the given supply situation. In any event, when the operator issatisfied with the elution schedule, it may be left alone to runautomatically as shown. With the elutions performed automatically, theoperator will be free to tend to other duties. Additionally, thesoftware provides a record of the elutions performed, simplifying recordkeeping purposes. Furthermore, while supply data screen 700 and elutionmanagement window 800 are tracking six generators, the present inventionscalable in that it is capable of monitoring as many generators as areincluded in the multiple generator elution system.

The present invention can provide cost savings to radio-pharmacies. Thelargest single cost for a radio-pharmacy is the Tc-99m/Mo99 generatorthat is used to compound the “cold kits” (the diagnostic agents). Anaction workout with experienced radio pharmacists, showed that theaverage pharmacy generator efficiency was 65-68%. Post implementation ofthe new tool average efficiency has steadily risen to 98-100%.Typically, an average pharmacy might consume four 18 Ci generators aweek. Each generator has a useful shelf life of two weeks. Thus on aweekly basis, the pharmacy would need to manage eight generators throughtheir decay and use cycles. Currently, using four 18 Ci units perweek@$7,000 each is a cost of $1.456 MM annually. If the same pharmacyimproves its efficiency from 65% to 100% by using the present invention,the annual cost is lowered by about $0.5 MM.

While the particular embodiment of the present invention has been shownand described, it will be obvious to those skilled in the art thatchanges and modifications may be made without departing from theteachings of the invention. The matter set forth in the foregoingdescription and accompanying drawings is offered by way of illustrationonly and not as a limitation. The actual scope of the invention isintended to be defined in the following claims when viewed in theirproper perspective based on the prior art.

1.-33. (canceled)
 34. A method of eluting a daughter nuclide from aplurality of parent-daughter generators, comprising the steps of:inputting the supply data comprising information allowing calculation ofthe available activity in the generators into an elution system;inputting demand data into the elution system, said demand datacomprising at least an amount of radioactivity of daughter nuclide to beproduced and a schedule for the production of the amount of daughternuclide; calculating and selecting the optimum elution schedule for eachof said plurality of generators based on said demand data, saidcalculating and selecting step comparing current demand, future demandand the available activity from said plurality of generators bothpresently and at a subsequent demand point so as to minimize waste ofdaughter isotope produced by said plurality of generators in meeting thedemand data; eluting the daughter nuclide from selected ones of saidplurality of generators according to the optimum elution schedule;collecting the daughter nuclide from each of said selected ones of saidplurality of generators in a concentration column; eluting the daughternuclide from said concentration column into a collection container. 35.A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 34, wherein said calculating andselecting step further comprises performing a Generalized ReducedGradient Algorithm analysis of the demand data and the activity levelsof the plurality of generators.
 36. A method of eluting a daughternuclide from a plurality of parent-daughter generators of claim 34,wherein said calculating and selecting step further comprises runningsimulations of various elution schedules from the plurality ofgenerators and selecting the elution schedule resulting in the lowestamount of waste of the daughter nuclide upon meeting the demand data.37. A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 34, wherein said step of inputtingdemand data further comprises entering the demand data into a receivingunit which provides the demand data to the control system.
 38. A methodof eluting a daughter nuclide from a plurality of parent-daughtergenerators of claim 37, wherein said step of inputting demand datafurther comprises the step of manually entering the demand data into areceiving unit which provides the demand data to the control system. 39.A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 37, wherein said step of inputtingdemand data further comprises the step of automatically entering thedemand data into a receiving unit electronically.
 40. A method ofeluting a daughter nuclide from a plurality of parent-daughtergenerators of claim 39, wherein said step of automatically entering thedemand data into a receiving unit electronically further comprises thestep of receiving the demand data from a web-based order processingsite.
 41. A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 37, wherein said calculating andselecting step is performed by a control system which receives thedemand data from the receiving unit.
 42. A method of eluting a daughternuclide from a plurality of parent-daughter generators of claim 34,wherein said inputting supply data step further comprises the steps ofinputting calibration data for each generators, the date and time thateach generator is available for use, the time and date of the firstelution off set for each generator.
 43. A method of eluting a daughternuclide from a plurality of parent-daughter generators of claim 34,wherein said calculating and selecting step considers the parent nuclidehalf-life, the parent nuclide decay equation, the daughter nuclidehalf-life, the daughter nuclide decay equation, the elution yieldefficiency, the fraction of elution available from the parent nuclidedecay, the equilibrium equation, and the expiration time for eachgenerator.
 44. A method of eluting a daughter nuclide from a pluralityof parent-daughter generators of claim 34, further comprising the stepsof: displaying the available activity in each of the plurality ofgenerators as calculated for a schedule of times; displaying the demanddata in a table at the schedule of times; and displaying the selectedelution schedule profile from said calculating and selecting step.
 45. Amethod of eluting a daughter nuclide from a plurality of parent-daughtergenerators of claim 44, further comprising the steps of: manuallyoverriding the selected elution schedule profile; calculating anoverride elution schedule profile resulting from said allowing step;displaying the override elution schedule profile said allowing step; andallowing an operator to one of confirm the override elution scheduleprofile and manually overriding the override elution schedule profile.46. A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 45, wherein said manually overridingsteps further comprise the steps of selecting which of the plurality ofgenerators will be eluted at a time of the schedule of times.
 47. Amethod of eluting a daughter nuclide from a plurality of parent-daughtergenerators of claim 34, wherein said step of inputting supply datafurther comprises the step of calculating the in-growth activity levelsof the selected ones of the plurality of generators after said elutingstep.
 48. A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 34, wherein said calculating andselecting step and said eluting step are performed by a control system.49. A method of eluting a daughter nuclide from a plurality ofparent-daughter generators of claim 48, wherein said control systemperforms each said eluting step according to the selected elutionprofile without further operator input. 50.-52. (canceled)
 53. Acomputer program product for managing the elution from a multiplegenerator elution system, comprising: a computer-usable medium havingcomputer-usable program code that manages a multiple generator elutionsystem, computer program product including: computer-usable program codethat receives inputted supply data for a number of parent-daughtergenerators; computer-usable program code receives demand data foractivity from the generators; computer-usable program code thatcalculates an elution schedule for the generators based on the availableactivity in the generators and the demand data; and computer programcode that directs an actuation system of the elution system to elutefrom selected ones of the generators according to the elution schedule.54. A computer program product of claim 53, further comprising computerprogram code for displaying at least one of the supply data, the demanddata, the available activity in the generators, and the elutionschedule.
 55. A computer program product of claim 53, wherein thecomputer program code that calculates an elution schedule furthercomprises computer program code for performing a Generalized ReducedGradient Algorithm analysis of the demand data and the activity levelsof the plurality of generators to determine the optimum elution schedulefor minimizing waste.
 56. A computer program product of claim 53,wherein the computer program code for calculating an elution schedulefurther comprises computer program code for running simulations ofvarious elution schedules from the plurality of generators and selectingthe elution schedule resulting in the lowest amount of waste of thedaughter nuclide upon meeting the demand data.
 57. A computer programproduct of claim 53, further comprising computer program code forallowing an operator to override the calculated elution schedule byinputting new constraints to the computer program product, and computerprogram code for calculating a new elution schedule based on the newconstraints.
 58. A computer program product of claim 53, furthercomprising computer program code for storing the supply data, the demanddata, and the elution schedule for future retrieval.
 59. (canceled)